Melatonin-Mediated Attenuation of Liver Injury Following Trauma-Hemorrhage---p38 Mapk Pathway

Trauma-hemorrhagic shock leads to hypoxia, microcirculatory derangement and secondary excessive production of inflammatory mediators, which is associated with multiple organ failure resulting in mortality or morbidity. Melatonin exerts an anti-inflammation and is a potent antioxidant. Treatment with pineal hormone melatonin following trauma-hemorrhagic shock improved immune functions, reduced fluid requirement and attenuated visceral organ injury. Short-term administration of melatonin attenuated organ damage in models of ischemia-reperfusion and inflammation, and improved survival in animals subjected to hemorrhagic shock and septic challenge. Studies in burn injury models also indicate that rats treated with melatonin significantly elevated the reduced glutathione levels while it decreased myeloperoxidase activity. The above-mentioned salutary effects of melatonin may be melatonin receptor-dependent. Furthermore, several rat tissues including the liver and intestine have been demonstrated to express melatonin receptors. Previous studies also showed that phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) was decreased in the liver and intestine 2 hours following trauma-hemorrhagic shock and fluid resuscitation, which in turn resulted in the production of cytokines/chemokines and more recruitment of neutrophil leading to liver or intestine damage. However, whether melatonin-mediated attenuation of liver injury after trauma-hemorrhage is through melatonin receptor dependent p38 MAPK pathway remains unclear. To test these hypotheses, we treated trauma-hemorrhage male rats before resuscitation and sham-operated with melatonin, melatonin plus p38 MAPK inhibitor SB203580, or melatonin plus melatonin receptor antagonist Luzindole. Two hour after trauma-hemorrhagic shock and resuscitation or sham operation, the effects of melatonin in different experimental groups were then explored through determining on liver injury markers including liver tissue myeloperoxidase (MPO) activity, malondialdehyde (MDA), adenosine triphosphate (ATP) and serum alanine aminotransferase (ALT) and asparate aminotransferase (AST), as well as phosphorylated p38 MAPK/p38 MAPK, inducible nitric oxide (iNOS), hypoxia-inducible factor (HIF)-1α protein expression and inflammatory mediators levels in the liver.

Project ID:PC10308-1862
External Project ID:MOST103-2314-B182-047